Lesch-Nyhan syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Lesch-Nyhan syndrome is a condition that is characterized by neurological and behavioral abnormalities and the overproduction of uric acid. Uric acid is a waste product of normal chemical processes and is found in blood and urine. Excess uric acid can be released from the blood and build up under the skin and in the joints. When uric acid builds up in the joints, it causes a form of arthritis called gouty arthritis. Uric acid accumulation can also cause kidney and bladder stones.

The first sign of Lesch-Nyhan syndrome is typically an orange color in the baby’s diaper that is caused by uric acid deposits in the urine. Babies with this condition often have normal development during the first few months of life, but they begin to experience developmental delays around 3 to 6 months. Affected babies can develop weak muscle tone (hypotonia) and involuntary muscle tensing (dystonia), which can interfere with crawling and walking.

During the first few years of life, children with Lesch-Nyhan syndrome can develop additional movement problems, such as muscle stiffness (spasticity); exaggerated reflexes (hyperreflexia); uncontrolled, jerking movements of the body (choreoathetosis); flailing of the limbs (ballismus); or episodes of muscle spasms that cause backward arching of the spine (opisthotonus). Over time, the movement problems become so severe that affected individuals require the use of a wheelchair and need help with personal care and other activities of daily living.

The characteristic feature of Lesch-Nyhan syndrome is self-injury. Affected individuals will often bite their lips, fingers, and cheeks. This behavior usually starts as soon as they develop teeth. Other, less common self-injurious behaviors can include eye-poking and banging of the head, arms, or legs. While the injurious behavior is typically self-directed, they may attempt to injure others. Although affected individuals feel the pain of the injuries, they have a compulsion to perform these behaviors.

Most individuals with Lesch-Nyhan syndrome develop a blood disorder called megaloblastic anemia. Megaloblastic anemia occurs when a person has a low number of red blood cells (anemia) and the remaining red blood cells are larger than normal (megaloblastic).

People with Lesch-Nyhan syndrome have a reduced life span; most affected individuals do not survive past early adulthood. Major health complications experienced by people with Lesch-Nyhan syndrome can include kidney failure, respiratory failure, and serious infections such as pneumonia.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Genetic changes that cause disease are called pathogenic variants. Pathogenic variants in the HPRT1 gene cause Lesch-Nyhan syndrome. The HPRT1 gene provides instructions for making an enzyme called hypoxanthine-guanine phosphoribosyltransferase (HGprt). This enzyme recycles purines, which are building blocks of DNA and its chemical cousin RNA. Recycling purines ensures that cells have a plentiful supply of building blocks for the production of DNA and RNA. Purines also play an important role in providing energy for cells.

The pathogenic variants in the HPRT1 gene that cause Lesch-Nyhan syndrome can severely reduce the amount of functional HGprt enzymes in cells or prevent cells from making this enzyme at all. Without HGprt, cells cannot recycle purines, so the purines are broken down. During this process, uric acid builds up in the body, resulting in gouty arthritis.

People with Lesch-Nyhan syndrome also have low levels of a chemical messenger in the brain called dopamine. Dopamine transmits messages that help the brain control physical movement and emotional behavior. It is likely that dopamine-producing cells need purines to function. When the supply of purines is low, dopamine-producing cells do not function well and dopamine levels decrease. This shortage of dopamine may play a role in the movement problems and other features seen in people with Lesch-Nyhan syndrome.

Although researchers understand some of the biological processes behind the development of Lesch-Nyhan syndrome, the exact cause of the neurological signs and symptoms of this condition is unclear.

Some people have pathogenic variants in the HPRT1 gene that allow cells to produce some functional HGprt enzymes. These individuals are said to have Lesch-Nyhan variant or partial HPRT1 deficiency. The signs and symptoms of Lesch-Nyhan variant are often milder than those of Lesch-Nyhan syndrome. People with Lesch-Nyhan variant often have high uric acid levels and may have neurological problems, but they do not injure themselves. Because Lesch-Nyhan syndrome and Lesch-Nyhan variant are caused by pathogenic variants in the same gene, they are sometimes considered to be part of the same disease spectrum.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Lesch-Nyhan syndrome is inherited in an X-linked pattern. A condition is considered X-linked if the altered gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes in each cell. In males (who have only one X chromosome), a variant in the only copy of the gene in each cell is sufficient to cause the condition. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

In females (who have two copies of the X chromosome), one altered copy of the gene typically does not cause features of the condition. Females with one HPRT1 gene variant should have about half of normal HGprt activity, but often the protein activity is normal. This is because the X chromosome that contains the variant may be turned off (inactive) in many of their blood cells due to a process called X-inactivation. Early in female embryonic development, one of the two X chromosomes is permanently inactivated in somatic cells (cells other than egg and sperm cells). X-inactivation ensures that females, like males, have only one active copy of the X chromosome in each body cell. Usually X-inactivation occurs randomly, such that each X chromosome is active in about half of the body's cells. However, in some cases, X-inactivation is not random, and one X chromosome is active in more than half of cells. When X-inactivation does not occur randomly, it is called skewed X-inactivation.

Females with a pathogenic variant in the HPRT1 gene often have skewed X-inactivation, which inactivates the X chromosome that contains the pathogenic variant in most blood cells.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Lesch-Nyhan syndrome almost exclusively affects boys and men. The prevalence of Lesch-Nyhan syndrome is approximately 1 in 235,000 to 380,000 individuals.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abnormality of movement · Very frequent (99-80%)

An abnormality of movement with a neurological basis characterized by changes in coordination and speed of voluntary movements.

Atypical behavior · Very frequent (99-80%)

Atypical behavior is an abnormality in a person's actions that can be controlled or modulated by the will of the individual. While abnormal behaviors can be difficult to control, they are distinct from other abnormal actions that cannot be affected by the individual's will.

Gout · Very frequent (99-80%)

Recurrent attacks of acute inflammatory arthritis of a joint or set of joints caused by elevated levels of uric acid in the blood which crystallize and are deposited in joints, tendons, and surrounding tissues.

Hemiplegia/hemiparesis · Very frequent (99-80%)

Loss of strength in the arm, leg, and sometimes face on one side of the body. Hemiplegia refers to a severe or complete loss of strength, whereas hemiparesis refers to a relatively mild loss of strength.

Hyperuricemia · Very frequent (99-80%)

The concentration of uric acid in the blood circulation is above the upper limit of normal.

Intellectual disability, mild · Very frequent (99-80%)

Mild intellectual disability (ID) is defined as a type of ID characterized by mildly sub-average adaptive functioning and intellectual functioning, with an intelligence quotient (IQ) the range of 50-69.

Intellectual disability, moderate · Very frequent (99-80%)

Moderate intellectual disability (ID) is defined as a type of ID characterized by moderately sub-average adaptive functioning and intellectual functioning, with an intelligence quotient (IQ) the range of 35-49.

Spasticity · Very frequent (99-80%)

A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.

Other findings in the same source

From: Orphanet

Additional reported features include Anemia (Frequent (79-30%)); Hematuria (Frequent (79-30%)); Renal insufficiency (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Lesch-Nyhan syndrome is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Lesch-Nyhan syndrome. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.